Down‐regulation of BRCA1 expression by miR‐146a and miR‐146b‐5p in triple negative sporadic breast cancers

Abstract

Germ-line mutations in the BRCA1 gene strongly predispose women to breast cancer (lifetime risk up to 80%). Furthermore, the BRCA1 protein is absent or present at very low levels in about one third of sporadic breast cancers. However, the mechanisms underlying BRCA1 somatic inactivation appear multiple and are still not fully understood. We report here the involvement of miR-146a and miR-146b-5p that bind to the same site in the 3′UTR of BRCA1 and down-regulate its expression as demonstrated using reporter assays. This was further confirmed with the endogenous BRCA1 gene by transfecting microRNA (miRNA) precursors or inhibitors in mammary cell lines. This down-regulation was accompanied by an increased proliferation and a reduced homologous recombination rate, two processes controlled by BRCA1. Furthermore, we showed that the highest levels of miR-146a and/or miR-146b-5p are found in basal-like mammary tumour epithelial cell lines and in triple negative breast tumours, which are the closest to tumours arising in carriers of BRCA1 mutations. This work provides further evidence for the involvement of miRNAs in sporadic breast cancer through down-regulation of BRCA1.

Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

“…17,18 Here, we chose to screen in familial breast cancer cases from the GENESIS study, the coding region of two miR genes, MIR146A and MIR146B, producing miR-146a and miR-146b-5p, respectively, as it has been shown that they regulate the expression of BRCA1. 12,13,19 A common MIR146A variant, rs2910164, which resides in the region encoding the sequence complementary to the mature miR in the stem-loop structure of the pre-miR, is one of the most extensively studied miR-related genetic variant. In the most recent meta-analysis published to date, no evidence of association between rs2910164 and breast cancer risk was obtained, although association was observed with bladder, cervical, liver and lung cancers, as well as with oral squamous cell carcinoma.…”

Recent trends in microRNA research into breast cancer with particular focus on the associations between microRNAs and intrinsic subtypes

“…Garcia et al reported that the highest levels of miR-146a and miR-146b-5p were found in BL in vitro and TNBC patients. 96 On the other hand, the BRCA1/2 gene is a well-characterized cancer susceptibility gene that is associated with hereditary breast and ovarian cancer. 97,98 Shen et al 99 suggested that genetic polymorphisms in the miR-146a gene might be associated with young age in familial cases of breast or ovarian cancer.…”

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

“…Although the ovarian cancer genome atlas reported a low incidence of mutations in other genes involved in the Fanconi complex, 256 there may be other mechanisms involved, including miRNA-mediated downregulation of BRCA1, 257 which has been reported in triple-negative breast cancers. 258 Anecdotically, a remarkable response to mitomycin was observed in a patient with pancreatic cancer harbouring biallelic PALB2 mutations. 259 Although PARP inhibitors administered as monotherapy was found ineffective in triple-negative breast cancer, experimental evidence has indicated synergistic lethality between cisplatin and PARP inhibitors in triple-negative breast cancer cells not harbouring BRCA1/2 mutations.…”